tbuckley/cabot-search huggingface dataset:
Chromosomal instability (CIN) in circulating tumor cells (CTC) predicts for taxane sensitivity in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Niamh M. Keegan, Andrea Arfe, Ethan Barnett, Erica Dayan Cohn, Jimmy Zhao, Emily Carbone, Michelle Zanone, Amanda Anderson, Rick Wenstrup, Howard I. Scher
Journal: Journal of Clinical Oncology (2022)

5026 Background: Few clinically validated biomarkers can inform therapy (tx) sequencing in mCRPC. Previously, we credentialed a biomarker of CIN in individual CTCs using phenotypic identification of cells with ≥9 large scale transitions (LSTs) and classification of CIN as high when detected in ≥3 CTC/mL (CIN3+). CIN3+ was associated with shorter radiographic progression survival (rPFS) and overall survival (OS) following taxane (T) or androgen receptor signaling inhibitor (ARSi) tx in mCRPC. Similarly, high CIN defined as ≥1 CTC/mL with ≥9 LSTs (CIN1+) predicts worse rPFS and OS following ARSi. Here, we explored if CIN1+ or CIN3+ predicted differential outcomes in pts on-tx with T or ARSi for mCRPC. Methods: We analyzed 208 banked CTC samples from 173 mCRPC pts collected within 30 days prior to starting a new tx with either T (n=88) or ARSi (n=120) in 2012-2017. CTCs were detected using Epic Sciences platform and CIN defined using the phenotypic classifier (PMID 32816908). Retrospective clinical annotation was completed for OS, defined as time from index tx start date to death, and rPFS, defined as index date to date of new or/and increasing lesion size in on-tx radiology report or death. Associations with rPFS and OS were studied according to samples’ CIN1+ and CIN3+ status. T vs. ARSi comparisons were adjusted using Cox models that incorporated pre-tx covariates, i.e. prior T or ARSi txs, total CTC count, presence of visceral disease, and prognostic lab values. Results: The median (range) follow-up from tx start to date of death or last follow-up was 7 (5-9) years. There were 53/120 (44%) pts starting ARSi that had prior ARSi txs and 41/88 (46%) pts starting taxane that had prior taxane txs. CTCs were detected in 184 (88%) samples, CIN1+ in 73 (35%; 64% pre-T, 36% pre-ARSi), and CIN3+ in 47 (22%; 60% pre-T,40% pre-ARSi). Compared to CIN1+, model results (Table) suggest that CIN3+ predicts a longer rPFS (p&lt;0.01), and possibly OS (p=0.05), with T therapy. Compared to CIN1-, CIN3- also predicts a longer OS with ARSi therapy (p=0.04). Conclusions: CIN3+ CTC may be a more discriminating predictive biomarker than CIN1+ to help guide selection of T or ARSi tx in pts with mCRPC. Adequately powered prospective studies are planned. [Table: see text]
DIPG-52. Activators of the integrated stress response synergize to kill DIPG
Authors: Orlandi Novak, Antje Arnold, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2022)

Abstract DIPG has elevated baseline activation of the integrated stress response (ISR), an evolutionarily conserved system that allows cells to tolerate various forms of stress. Increased expression of activating transcription factor 4 (ATF4) indicates activation of the ISR. Intermediate levels of ATF4 protect cells from stress, while sustained high levels result in cell death. The imipridone drug ONC201 binds to and activates the mitochondrial protease ClpP, leading to increased mitochondrial stress and persistent ATF4 activation. Because DIPG has a high baseline level of ATF4, we hypothesized that the ISR activators Sal003, ONC201, and fenretinide would synergize to kill DIPG. Sal003 inhibits dephosphorylation of ATF4 upstream regulator, eIF2α. The retinoic acid derivative fenretinide induces ATF4, increases reactive oxygen species, and has clinical activity in pediatric patients with neuroblastoma. After determining the IC25 of Sal003, fenretinide, and ONC201, we treated patient-derived DIPG cell lines with low micromolar doses. The combination of Sal003 and ONC201 significantly increased apoptosis as measured by CC3 immunofluorescence in comparison to DMSO (p&amp;lt;0.0001, ANOVA). Combination therapy also significantly increased CC3 positivity compared to single treatment. Western blots for cleaved PARP expression detected induction of apoptosis in DIPG treated with both Sal003 and ONC201 over DMSO and monotherapy treated cells. In some cell lines, the combination increased ATF4 expression. Since Sal003 is not yet available for clinical testing in humans, we treated DIPG cells with ONC201 and fenretinide. CC3 immunofluorescence indicated synergistically elevated apoptosis in the combination of ONC201 and fenretinide vs. DMSO (p&amp;lt;0.0001, ANOVA). Western blots showed increased cleaved PARP, ATF4, and CHOP expression in DIPG treated with ONC201 and fenretinide. We are currently testing the efficacy of this combination in orthotopic DIPG xenografts. Our results suggest the combination of ONC201 with fenretinide could potentially serve as a therapy for DIPG.
The effect of COVID-19 outbreak on endourological treatments for urinary stones: A retrospective multicentric study
Authors: G. Mazzon, S. Ferretti, P. Acquati, S. Nazzani, D. Campobasso, F. Germinale, B. Filippi, S. Micali, N. Pavan, G. De Marco, A. Vismara Fugini, T. Morena, A. Peroni, G. Celentano, M. Creta, E. Serafin, G. Costa, B. Rocco, U. Maestrani, C. Vaccaro, L. Carmignani, C. Trombetta, M.A. Cerruto, A. Antonelli, A. Celia
Journal: European Urology (2022)
Safety of the cyclin dependent kinase 9 (CDK9) inhibitor FIT039 for cervical intraepithelial neoplasia (CIN) 1 or 2 in a phase I/II trial.
Authors: Junzo Hamanishi, Eriko Sumi, Taito Miyamoto, Ryuji Uozumi, Koji Yamanoi, Harue Tada, Yoko Amino, Yu Hidaka, Masayo Ukita, Ken Yamaguchi, Ryuta Asada, Masahiko Ajiro, Teruo Sawada, Masatoshi Hagiwara, Masaki Mandai
Journal: Journal of Clinical Oncology (2022)

3022 Background: Human papillomaviruses (HPVs) infect uterine cervical epithelial cells, leading to cervical intraepithelial neoplasia (CIN) and cervical cancer. However, there is no treatment for HPV infection in the uterine cervix prior to vaccination. We recently reported that cyclin dependent kinase 9 (CDK9) plays a critical role in viral RNA transcription of DNA viruses such as HPVs in host cells, and that FIT-039, a specific inhibitor of CDK9, suppresses the proliferation of several DNA viruses. Here, we evaluated the safety and antiviral effect of a FIT039-releasing vaginal tablet (FIT039CT) for CIN1 or 2 (CIN1/2). Methods: A multi-institutional, single-blind, placebo-controlled randomized phase I/II clinical trial involving 2 cohorts was designed to evaluate the safety of transvaginal FIT039CT for CIN1/2 as follows:. In the first cohort, 8 healthy women were randomized into FIT039CT (50mg/day or 100mg/day) or control group. In the second cohort, 14 women with a primary diagnosis of CIN1/2 were randomized into either FIT039CT (100mg/day) or control group. The primary endpoints were adverse events and plasma concentrations of FIT039. Results: 22 patients (8 volunteers, 11 CIN1 and 3 CIN2) were enrolled. There were no serious adverse events. Adverse events considered related to treatment were mild (vaginal discharge Grade 1: FIT039CT 16/17 women [94%] vs placebo 2/6 [33%]) and self-limiting in both cohorts. No patient discontinued this study due to adverse events. Maximum concentration (C max) and terminal elimination half-life (t 1/2) of serum FIT039 concentrations after single transvaginal treatment of FIT039CT were similar between the two doses as follows; C max (mean ± standard deviation) was 4.5 ± 0.5 ng/mL (50mg/day) and 4.4 ±1.4 ng/mL (100mg/day) at 6-7 hours; mean t1/2 was 14.8 ± 2.1 hours (50mg/day) and 12.1 ± 2.6 hours (100mg/day) hours. Conclusions: This study demonstrated the safety and validity of transvaginal FIT039CT once a day and may contribute to the development of an antiviral agent that can cure CIN1/2, and supports the design of the ongoing phase 2 clinical study. Clinical trial information: jRCT2051180201.
Impact of personalized care discussions on advance care planning.
Authors: Emma Hannan, Elizabeth Collins, Lindsay Wilde, Brooke Worster, Molly Hanson, Valerie Pracilio Csik, Nathan Handley, Jillian VanSciver
Journal: Journal of Clinical Oncology (2022)

e18619 Background: Advanced Care Planning (ACP) involves learning about decisions that may need to be made during care so they are known to family and providers. ACP has been associated with less aggressive medical care near death and improved quality of life. However, despite evidence for their benefit, ACP is inconsistent among patients with advanced cancer. At our institution, only 52% of patients with cancer undergoing palliative intent treatment had an ACP at the time of death. We sought to increase ACP through a quality improvement project intended to proactively identify and introduce patients to Personalized Care Discussions (PCDs). PCDs engage oncology patients and palliative care providers in ACP to articulate goals of care. Methods: A team of palliative care providers, medical oncologists, and administrative staff designed each phase of the intervention. Inclusion criteria to proactively identify patients eligible for a PCD were created along with a workflow to introduce PCDs and schedule a PCD appointment. A plan-do-study-act (PDSA) model was used to test impact of change to the PCD referral workflow and patient inclusion criteria. Each PDSA cycle lasted between 4 and 9 weeks between 6/1/2021 and 1/31/2022. PDSA 1: Oncologist referral to PCD for new patients. PDSA 2: Oncologist referral to PCD for Stage IV patients. PDSA 3: Automatic referral to PCD of Stage IV patients. PDSA 4: Pancreatic patients, any stage, added to PDSA 3 criteria. Results: During the measurement period, 68 patients completed a PCD. While changes to the inclusion criteria throughout PDSA cycles resulted in more total unique patients completing PCDs, the completion rate of eligible patients did not vary significantly across cycles. However, the proportion of patients completing PCDs for oncologists engaged in the project increased during the eight-month QI period (92%) from the previous eight-month period (86%). Conclusions: This project sought to identify and introduce patients to PCDs to improve ACP. We found that access to PCDs was not sufficient to increase completion of PCDs, since fewer than half completed the appointment. However, 68 patients who otherwise may not have completed a PCD did so because of this intervention. Misperceptions of palliative care may contribute to high cancellation rates of PCD appointments. This pattern is seen in the overall low completion rate of palliative care appointments (56% in same timeframe). Informal patient feedback often indicated a preference for care discussions to be with the primary oncologist, whereas our intervention introduced a new provider. These results demonstrate that a trigger to identify patients for PCDs without primary oncologist engagement falls short. Continued focus is needed to determine a proactive approach to identify patients who will benefit most from PCDs to complete ACP proactively.[Table: see text]
Predicting recurrence of venous thromboembolism in anticoagulated cancer patients using real-world data and machine learning.
Authors: Andrés J. Muñoz Martín, Sofía Huerga Domínguez, Juan Carlos Souto, Jacobo Rogado Revuelta, Antonio Sanchez, Andres Garcia-Palomo, Jorge Aparicio, Cristina Aguayo, David Gutierrez Abad, Laura Ortega, Maria Carmen Viñuela-Benéitez, Victor Fanjul, David Casadevall, Daniel Arumi, Miguel Ángel Hernández-Presa
Journal: Journal of Clinical Oncology (2022)

e18742 Background: The clinical predictors of venous thromboembolism (VTE) recurrence in patients with cancer are not well known. Our objective was to develop a predictive model for risk of VTE recurrence in anticoagulant-treated cancer patients within the first 6 months following VTE diagnosis. Methods: Using the EHRead technology, based on Natural Language Processing (NLP) and machine learning (ML), the unstructured clinical data in EHRs from 9 Spanish hospitals between 2014 and 2018 was extracted and analyzed. The study population, comprising all adult anticoagulated cancer patients with VTE, was downsampled to prevent bias and class imbalance. A total of 94 patient characteristics were explored, and Random Forest (RF) feature selection was performed to identify the most relevant predictors for VTE recurrence. Multiple algorithms were used to train different prediction models, which were subsequently validated in a hold-out dataset. The model with the best performance metrics (i.e., ROC-AUC) was selected as the final model. Results: From a source population of 2,893,208 patients, 21,227 anticoagulant-treated patients with VTE and active cancer (53.9% male, median age of 70 years) were identified. Across the study period, yearly incidence of VTE remained relatively stable, ranging from 2.7 to 3.9%. The most common type of VTE was deep vein thrombosis (68.2% of patients), followed by pulmonary embolism (28.4%). Regarding primary cancer locations, the most frequent were colorectal (10.1%) and lung cancer (8.5%). Of all trained and validated models, the RF approach yielded the best performance, with a ROC-AUC = 0.72. The following predictors of VTE recurrence were identified: pulmonary embolism, deep vein thrombosis, metastasis, adenocarcinoma, hemoglobin values, serum creatinine values, platelet count, leukocyte count, family history of VTE, and patients’ age. Conclusions: Using NLP and ML, we were able to use the real-world data in EHRs to build a predictive model of VTE recurrence in cancer patients based on individual clinical features. These results may improve the clinical management of VTE recurrence in this population.
Burden of insomnia among cancer patients undergoing treatment: A retrospective claims database analysis.
Authors: Emerson M Wickwire, Timothy R Juday, Feride H Frech, Mona Arti Kelkar, Jihaeng Heo, Manoj Malhotra
Journal: Journal of Clinical Oncology (2022)

e18816 Background: Almost half of all cancer patients have trouble sleeping, usually insomnia or other sleep-wake disorders. Cancer treatment can exacerbate sleep problems. This study evaluated all-cause healthcare resource utilization (HCRU) and costs in cancer patients undergoing treatment who also have insomnia relative to a matched cohort of cancer patients undergoing treatment who do not have insomnia. Methods: This retrospective study used the IBM MarketScan Commercial and Medicare Supplemental Databases (Jan 2014-Dec 2019) to identify patients: (1) age ≥18 years; (2) with ≥1 ICD-9/ICD-10 codes for insomnia OR with ≥2 prescriptions for zolpidem immediate release (IR) OR trazodone ≤150mg OR benzodiazepine; (3) with ≥12 months of continuous enrollment pre-/post-index date (earliest diagnosis or medication fill date); (4) with ≥2 ICD-9/ICD-10 codes for any cancer; and (5) ≥1 claim for oncology treatment. Patients with sleep disorders other than insomnia were excluded. The resulting patients (“insomnia cohort”) were 1:1 matched on age, sex and Elixhauser Comorbidity Index (ECI) score to patients with cancer undergoing treatment without insomnia or other sleep disorders (“control cohort”). HCRU and costs were reported per patient per month (PPPM). Generalized linear models were used to compare adjusted outcomes between cohorts. Results: For each cohort, 7,132 patients (mean age 60.8 years, 69.5% female, 13.6 ECI score) were identified. In adjusted analyses, significantly more patients in the insomnia cohort had at least one inpatient visit per month, inpatient stays were significantly longer, and mean outpatient visits were significantly higher (all p &lt; 0.001) relative to the control cohort. The insomnia cohort had higher mean number of emergency department (ED) visits (p &lt; 0.05); however, mean number of inpatient visits was not significantly different between cohorts. Adjusted analyses also showed significantly higher mean total PPPM costs for the insomnia cohort than the control cohort ($4,864 and $3,302, respectively; mean ratio = 1.47; p &lt; 0.0001). Mean PPPM costs for inpatient visits, ED visits, and outpatient costs were also higher for the insomnia cohort (p &lt; 0.001). Conclusions: Cancer patients undergoing treatment who have insomnia had more intensive HCRU and higher costs relative to those without insomnia. These results suggest that better managing insomnia in this population may have a beneficial impact on both patients and payers.
A full time job: a year with early-stage breast cancer
Authors: Elizabeth Lerner Papautsky
Journal: BMJ (2022)

A full time job: a year with early-stage breast cancer Elizabeth Lerner Papautsky researcher in patient safetyNobody told me that breast cancer is a full time job.In my case-stage 2 invasive ductal carcinoma, a type responsible for 80% of cases-it turned out to be a job that doesn't care that you have other responsibilities-two small children, a spouse, a career.
Genetic determinants of mannose-binding lectin activity predispose to thromboembolic complications in critical COVID-19
Authors: Michael Hultström, Robert Frithiof, Jonathan Grip, Linnea Lindelöf, Olav Rooijackers, Sara Pigazzini, Mari Niemi, Mattia Cordioli, Lindo Nkambule, Tomislav Maricic, Kristina Nilsson Ekdahl, Bo Nilsson, Miklós Lipcsey, Hugo Zeberg, Oskar Eriksson
Journal: Nature Immunology (2022)
Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR) and Lymphocyte-Monocyte Ratio (LMR) in predicting Systemic Inflammatory Response Syndrome (SIRS) and sepsis after Percutaneous Nephrolithotomy (PNL)
Authors: A.K. Chawla, A. Kriplani, S. Pandit, A. Choudhary
Journal: European Urology (2022)
Effect of performance status (ECOG PS) on treatment outcome with second-line (2L) nintedanib (NIN) + docetaxel (DOC) for patients (pts) with lung adenocarcinoma after first-line (1L) immune checkpoint inhibitor (ICI) combination therapy.
Authors: Christian Grohé, Thomas Wehler, Sven Henschke, Ina Dittrich, Stefan Hammerschmidt, Christoph Aulmann, Tobias Dechow, Conrad Schiefer, Ingo Zander, Wolfgang Schuette, Judith Atz, Rolf Kaiser
Journal: Journal of Clinical Oncology (2022)

9092 Background: ICIs with or without chemotherapy represent 1L standard of care for patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. Given the paucity of prospective randomized trials assessing second-line treatment options post-immunochemotherapy, non-interventional data may help support clinical decision making. Patients with ECOG PS &gt; 1 are generally underrepresented in clinical trials relative to routine clinical practice. We therefore examined treatment outcomes with 2L NIN + DOC after 1L ICI combination therapy with respect to ECOG PS at baseline. Methods: In this analysis of Cohort C of the ongoing, non-interventional VARGADO study (NCT02392455), eligible pts had locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC and received 2L NIN+DOC in routine clinical practice after failure on 1L ICI in combination with chemotherapy. The primary endpoint is 1-year survival rate (not yet mature). Tumor response was according to investigator review. Results: In 164 pts enrolled in Cohort C, median age was 63 years (range: 37 – 84), 100 pts (61.0%) were men, and 123 pts (75.0%) were ECOG PS 0–1. 146 pts (89.0%) had received prior 1L pembrolizumab-based combination therapy. Objective response rate (ORR) with 2L NIN+DOC was 35.4% (40/113 pts) in the overall population and 41.2%, 30.8% and 28.6% for pts with ECOG PS 0, 1 and &gt; 1, respectively. Disease control rate (DCR) was 67.3% (76/113 pts) in the overall population and 76.5%, 65.4% and 50.0% for pts with ECOG PS 0, 1 and &gt; 1, respectively. Median PFS was 4.7 months (95% CI: 3.4 – 5.3) in the overall population and 5.1 months (95% CI: 2.8 – 8.3), 3.7 months (95% CI: 2.5 – 5.3) and 2.1 months (95% CI: 1.3 – 6.5) for pts with ECOG PS 0, 1 and &gt; 1, respectively. The median OS was 8.1 months (95% CI: 6.3 – 11.2) in the overall population and 9.1 months (95% CI: 5.4 – 14.5), 10.5 months (95% CI: 6.3 – 14.9) and 4.0 months (95% CI: 2.5 – 6.3) for pts with ECOG PS 0, 1 and &gt; 1, respectively. Conclusions: Our results support 2L NIN+DOC as an effective treatment option in pts with advanced adenocarcinoma NSCLC following 1L ICI in combination with chemotherapy. ECOG PS &gt; 1 was associated with lower ORR, DCR and shorter PFS and OS. These findings warrant further evaluation of the effect of ECOG PS on 2L treatment outcomes in patients after 1L ICI combination therapy. Clinical trial information: NCT02392455.
Shockwave lithotripsy for distal ureteric stones: Real world outcomes from the Endourological Society T.O.W.E.R. research initiative
Authors: F.C. Gabrigna Berto, H. Razvi, J. Bjazevic, V.K.F. Wong, L. Nott, D. Golomb, M. Hossny, R. Dasgupta, P.J.S. Osther, B. Turney, B.H. Chew
Journal: European Urology (2022)
DDEL-05. Intraventricular therapy with topotecan is feasible and safe: Experience in 50 pediatric patients with various malignant brain tumors
Authors: Andreas Peyrl, Natalia Stepien, Lisa Mayr, Amedeo Azizi, Johannes Gojo, Alicia Baumgartner, Cora Hedrich, Maria Aliotti Lippolis, Irene Slavc
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Malignant brain tumors carry a high risk for leptomeningeal dissemination, but the CSF compartment is often not affected by systemic therapy. Intraventricular therapy via an Ommaya reservoir is one possibility to increase the cytotoxic drug concentration in the CSF. Unfortunately, the number of drugs that can be administered directly into the CSF is limited. We report on our experience with topotecan administered via an Ommaya reservoir. PATIENTS AND METHODS: Between 2015 and 2021, 50 patients aged 1 to 22 years (mean and median both 8 years) with various malignant brain tumors received intraventricular topotecan via an Ommaya reservoir. Topotecan was administered at 0.4mg twice a week (&amp;gt;1 and &amp;lt;2 years 0.25mg, &amp;gt;2 and &amp;lt;3 years 0.32mg). RESULTS: In total, 1168 doses of topotecan (1-87/patient, mean 23, median 18) were administered at our department. Treatment was given over a period of 0-65 months (mean and median 33 months). Intraventricular treatment with topotecan was generally well tolerated. Two patients reported side effects. One boy with multiple recurrences of an ependymoma in the posterior fossa showed increased tremor after intraventricular administration of topotecan, another girl with recurrent medulloblastoma reported fatigue. CONCLUSION: Intraventricular therapy with topotecan is feasible and generally well tolerated. Topotecan can be an important addition for patients with recurrent malignant brain tumors to increase cytotoxic drug concentrations in CSF.